Anxiety disorders that are linked to events or things (e.g. post-traumatic stress disorder (PTSD), phobias) would benefit from the simultaneous mitigation of the anxiety as well as the memories associated with the inducing event. Although currently available anxiolytics are able to treat acute anxiety, they have been shown to impair the formation of new memories. The symptoms of some anxiety disorders respond to acute and fast acting benzodiazepines (e.g. initial and short-term treatment of panic disorder and generalized anxiety disorder). However, others, such as PTSD, have persistent, highly intrusive symptoms (flashbacks) that are resistant to current treatments. Moreover, PTSD has high comorbidity with depression, suicide, and drug abuse, which are themselves difficult to treat especially in the presence of a debilitating anxiety disorder. A selective pharmacotherapy that can both reduce anxiety within therapy sessions and is memory enhancing is lacking. The neuropeptide S system has one endogenous ligand (NPS) and one receptor (NPSR) whose expression is relatively restricted. The therapeutic potential for the NPS-system resides in its unique behavioral profile, which is distinct from most systems. Central administration of NPS in mice enhances learning, increases arousal and produces anxiolytic-like effects. Discovery of small molecule NPSR agonists, let alone biased agonists has been extremely difficult. To our knowledge, no small molecule agonists have been disclosed in the patent or peer reviewed literature. Based on research conducted in our lab, we have identified the first and only biased, small molecule, NPS scaffold that retains full agonist properties in calcium mobilization assays, but has attenuated ability to increase cAMP levels. This is distinct from the native peptide (NPS) that displays roughly equal efficacy for both second messenger pathways. One of our biased agonists produces similar anxiolytic and memory enhancing effects as NPS in mice and can be blocked with RTI-118 a potent NPS antagonist. Based on this data we hypothesize biased agonists of the neuropeptide S receptor (NPSR) lacking cAMP activation will be useful for treating PTSD and other anxiety disorders where memory promotion is beneficial. The chemistry component of this application aims to improve NPSR potency, maintain signaling bias, and enhance drug-like properties of the lead compounds. The behavioral component of the application will focus on further establishing the behavioral profiles for our biased agonists. These aims will be accomplished through a collaboration of chemistry, in vitro pharmacology, and behavioral pharmacology programs.